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Advancing Cancer Vaccines

A Drug Class Almost Ready to Take Off

The cadre of speakers extolling the virtues of therapeutic cancer vaccines at the recent “World Vaccine Congress” in Lyon, France, included Vincent Brichard, M.D., Ph.D., vp, cancer immunotherapeutics, GlaxoSmithKline Biologicals (www.gsk-bio.com). “Many would say that therapeutic cancer vaccines have experienced 20 years of failure, but I would say it has been 20 years of valuable learning that we are now ready to build on,” said Dr. Brichard.

Therapeutic cancer vaccines, a broad term for a DNA-, cell-, or protein-based drug designed to stimulate the immune system to initiate a cytotoxic reaction against cancer cells, look to be enjoying renewed interest, and Jean-Yves Bonnefoy, Ph.D., vp of R&D at Transgene (www.transgene.com), explained why.

“Investment in therapeutic cancer vaccines is being buoyed along by the market success of prophylactic cancer vaccines such as Merck’s Gardasil and GSK’s Cervarix. This year, TG4001, our cervical cancer vaccine, was licensed by Roche, and Oxford Biomedica’s TroVax renal cancer therapy was snapped up by sanofi-aventis.

“This is a sea change from the past five years when many big pharmas wouldn’t touch therapeutic cancer vaccines because they believed the vaccines didn’t actually work.” Despite the newfound optimism by big pharma, the first approval of a therapeutic cancer vaccine remains elusive.

In the past decade, therapeutic cancer vaccines have been developed mainly by small biotechs that were so strapped for cash they ran short trials to generate rapid results. This led to many cancer vaccines being developed to treat melanoma, pancreatic, or prostate cancer.

These diseases, however, are capable of rapid replication, and disease progression can be recorded before an effective immune response is generated so it is difficult to tell if the vaccine is working using disease progression as a clinical endpoint.

Dendreon (www.dendreon.com) typifies this tale, but its results also underscore the promise of cancer vaccines. The company’s failure to gain regulatory approval this year for sipuleucel-T (Provenge), its autologous-blood, antigen-presenting cell therapy to treat prostate cancer, has been well publicized.

“It has been a roller-coaster ride this year as our BLA for Provenge has been under review,” said David Urdal, Ph.D., CSO of Dendreon. “Provenge just missed its primary endpoint, time-to-disease progression, but it demonstrated a survival outcome in a double-blind, randomized, controlled trial that favored Provenge over placebo. Men assigned to the Provenge arm had a median survival of 4.5 months longer than men assigned to the placebo arm. There was a 41 percent overall reduction in the risk of death with Provenge.

“We learned in this trial that progression of metastatic, androgen-independent prostate cancer is much more rapid than we thought (eight to ten weeks), and measuring time-to-disease progression with a drug that needs time to mount an immune response can be challenging.” Dr. Urdal noted that in contrast, survival is measured in months and may be the best endpoint to use for these types of agents.

“The other useful information we discovered is that patients given Doxitaxel chemotherapy after Provenge treatment may also have better survival rates, so Provenge could be an important new tool for improving the effectiveness of Doxitaxel.

“As Provenge is well tolerated and shows a survival outcome in the studies we submitted in our BLA, the FDA will allow us to submit survival-rate data from our other ongoing Phase III study to amend our BLA and provide additional evidence in support of our efficacy claim,” Dr. Urdal concluded. “We’ll have our first opportunity to see interim data in 2008, so we remain hopeful that Provenge could still be the first therapeutic cancer vaccine approved.”

Showing Promise

Despite Dendreon’s woes, there are scores of biotech companies still developing therapeutic vaccines for cancers that are difficult to treat with an immunotherapy. Immatics Biotechnologies’ (www.immatics.com) lead compound, IMA901, is a mixture of 10 tumor-associated peptides in water, administered intradermally together with a GM-CSF adjuvant.

“We identified more than 2,000 HLA-binding peptides from human renal tumor tissue,” Niels Emmerich, Ph.D, COO at Immatics, explained. “From these we then eliminated peptides that were not tumor-associated, nonimmunogenic, too hydrophobic, or have IP issues around them.

“From the remaining five percent of peptides, we selected ten for use in IMA901 formulation that bind to HLA-A*02 and activate cytotoxic T cells. The cost of goods for producing IMA901 will be attractive too as we can manufacture using solid-phase chemistry in ton quantities without the need for cell culture.”

According to Dr. Emmerich, in a Phase I study of 28 patients, IMA901 was safe and well tolerated. Also 75% of patients had an immune response to at least one peptide in IMA901, and shrinkage of tumor lesions was seen. On the basis of these results, Immatics began a Phase II study of over 70 patients with metastatic renal cell cancer in September.

“Late-stage renal cell carcinoma is a difficult cancer to treat and in an ideal world we would be treating earlier stages of the disease,” Dr. Emmerich said. “But with the level of funding we have available we have to get proof-of-concept data rapidly so we are taking a risk that we strongly believe will pay off and will demonstrate efficacy of this approach by early 2009.”

In-licensing

Even though there are still concerns about lack of efficacy of therapeutic cancer vaccines, GSK and Roche think there is promise and have thrown their hats in the ring—Roche by in-licensing from Transgene and GSK by developing a recombinant melanoma antigen (MAGE-A3) licensed from the Ludwig Institute for Cancer Research.

Dr. Brichard presented data on GSK’s antigen-specific cancer immunotherapeutic approach using MAGE-A3 to treat non-small-cell-lung cancer. “MAGE-A3 is present on many tumor cells including non-small-cell-lung, head and neck, and bladder cancer but is not found on the surface of any healthy cell type so it is a genuine target,” Dr. Brichard stated.

“We have chosen to develop its use as a lung cancer vaccine because MAGE-A3 expression is present in over 50 percent of stage III non-small-cell-lung cancer patients and is also associated with poor survival rates in this disease, so it is worthwhile to try to target this antigen.”

According to Dr. Brichard, the MAGE-A3 antigen-based vaccine is being produced in E. coli using proprietary vector technology. The protein, however, requires a complex purification and robust manufacturing process. Therefore, it would be difficult for a biosimilars company to replicate. The MAGE-A3 antigen, which is given in combination with GSK’s adjuvant system, stimulates CD4+ T cells to recognize tumor cells and initiate an immune response against them, leading to tumor cell death.

Dr. Brichard demonstrated the efficacy of this approach with data from a Phase II double-blind, placebo-controlled study of 182 patients with stage IB or II non-small-cell-lung cancer, which showed that after 28 months there was a 27% reduction in the relative risk of cancer recurrence following surgery, compared with placebo.

“Based on our promising Phase II data, we are beginning a Phase III trial of over

2,200 patients,” Dr. Brichard noted. “This is the biggest clinical trial ever conducted in lung cancer treatment, and we hope to have some initial results by 2010. By conducting such a large trial, we are really opening the door on therapeutic cancer vaccines as a new drug class.”

The other vaccine set to go into large Phase III trials is TG4001 (now renamed R3484), Transgene’s HPV vaccine to treat CIN 2/3. “R3484 is a modified virus Ankara nonpropagating, attenuated vaccinia virus backbone into which DNA for HPV 16 associated antigens (E6 and E7) and interleukin 2 is engineered,” Dr. Bonnefoy said.

In a Phase II trial of 21 women, 25–44 years old, with cervical cancer lesions, 12 months post-R3484 vaccination 10 women had no lesions present, which meant they did not need cone biopsy surgery, Dr. Bonnefoy noted. “R3484 could offer a great alternative to surgery, and this is important as many women in this age group still want to have children naturally, and they may not after this surgery. Building on these encouraging Phase II results, we are going to begin a placebo-controlled Phase III trial of R3484 with around 800 women in Europe and the U.S. early next year.”

Looking Ahead to 2010

Speakers at the “World Vaccine Congress” agreed that therapeutic cancer vaccines still have many obstacles to overcome before they reach the market—the main one still being proof of efficacy.

Delegates at the Congress were upbeat about the future. Dr. Bonnefoy summed it up nicely when he said, “Many clinicians are interested in therapeutic cancer vaccines, so we get good commitment at the trial level in terms of recruitment and compliance.

With the major pharmas beginning to come on board to fund large trials, we are hopeful that Roche, for example, can not only help provide enough data to prove efficacy, but also raise the profile of therapeutic vaccines just as it did for monoclonal antibody therapy with Genentech’s Herceptin. By 2010 we could finally see this new class of drug with a low side-effect profile getting to those cancer patients who really need it.”

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